Familial hypercholesterolaemia: a model of care for Australasia.
Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma cholesterol and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but the vast majority remains undetected and those diagnosed with the condition are inadequately treated. To bridge this major gap in coronary prevention the FH Australasia Network (Australian Atherosclerosis Society) has developed a consensus model of care (MoC) for FH. The MoC is based on clinical experience, expert opinion, published evidence and consultations with a wide spectrum of stakeholders, and has been developed for use primarily by specialist centres intending starting a clinical service for FH. This MoC aims to provide a standardised, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. The MoC for FH is presented as a series of recommendations and algorithms focusing on the standards required for the detection, diagnosis, assessment and management of FH in adults and children. The process involved in cascade screening and risk notification, the backbone for detecting new cases of FH, is detailed. Guidance on treatment is based on risk stratifying patients, management of non-cholesterol risk factors, safe and effective use of statins, and a rational approach to follow-up of patients. Clinical and laboratory recommendations are given for genetic testing. An integrative system for providing best clinical care is described. This MoC for FH is not prescriptive and needs to be complemented by good clinical judgment and adjusted for local needs and resources. After initial implementation, the MoC will require critical evaluation, development and appropriate modification.


Adult respiratory distress syndrome secondary to end-stage liver disease-successful outcome following liver transplantation.
The adult respiratory distress syndrome (ARDS) complicating liver failure carries a 100% mortality. Two cases of ARDS that resolved following liver transplantation have been reported, one associated with acute allograft rejection, and the second due to sepsis. There is, however, a great reluctance to transplant these very-high-risk patients. We report the first series of patients with ARDS secondary to liver failure who successfully underwent OLTX. No patient had sepsis or pneumonia. Posttransplant mechanical ventilation was required for a median of 14 days (range 6-37 days). All patients in this series are alive and well, with a follow-up of 6-15 months. This demonstrates that ARDS associated with liver failure, an otherwise uniformly lethal complication, can respond dramatically to OLTX.


International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people.
These recommendations were systematically developed on behalf of the Network for Early Onset Cystic Kidney Disease (NEOCYST) by an international group of experts in autosomal dominant polycystic kidney disease (ADPKD) from paediatric and adult nephrology, human genetics, paediatric radiology and ethics specialties together with patient representatives. They have been endorsed by the International Pediatric Nephrology Association (IPNA) and the European Society of Paediatric Nephrology (ESPN). For asymptomatic minors at risk of ADPKD, ongoing surveillance (repeated screening for treatable disease manifestations without diagnostic testing) or immediate diagnostic screening are equally valid clinical approaches. Ultrasonography is the current radiological method of choice for screening. Sonographic detection of one or more cysts in an at-risk child is highly suggestive of ADPKD, but a negative scan cannot rule out ADPKD in childhood. Genetic testing is recommended for infants with very-early-onset symptomatic disease and for children with a negative family history and progressive disease. Children with a positive family history and either confirmed or unknown disease status should be monitored for hypertension (preferably by ambulatory blood pressure monitoring) and albuminuria. Currently, vasopressin antagonists should not be offered routinely but off-label use can be considered in selected children. No consensus was reached on the use of statins, but mTOR inhibitors and somatostatin analogues are not recommended. Children with ADPKD should be strongly encouraged to achieve the low dietary salt intake that is recommended for all children.


Menstrual cycle effects on attitudes toward romantic kissing.
Hormonal changes associated with the human menstrual cycle have been previously found to affect female mate preference, whereby women in the late follicular phase of their cycle (i.e., at higher risk of conception) prefer males displaying putative signals of underlying genetic fitness. Past research also suggests that romantic kissing is utilized in human mating contexts to assess potential mating partners. The current study examined whether women in their late follicular cycle phase place greater value on kissing at times when it might help serve mate assessment functions. Using an international online questionnaire, results showed that women in the follicular phase of their menstrual cycle felt that kissing was more important at initial stages of a relationship than women in the luteal phase of their cycle. Furthermore, it was found that estimated progesterone levels were a significant negative predictor for these ratings.


Five-stage free-space optical switching network with field-effect transistor self-electro-optic-effect-device smart-pixel arrays.
The design, construction, and operational testing of a five-stage, fully interconnected 32 × 16 switching fabric by the use of smart-pixel (2, 1, 1) switching nodes are described. The arrays of switching nodes use monolithically integrated GaAs field-effect transistors, multiple-quantum-well p-i-n detectors, and self-electro-optic-device modulators. Each switching node incorporates 25 field-effect transistors and 17 p-i-n diodes to realize two differential optical receivers, the 2 × 1 node switching logic, a single-bit node control memory, and one differential optical transmitter. The five stages of node arrays are interconnected to form a two-dimensional banyan network by the use of Fourier-plane computer-generated holograms. System input and output are made by two-dimensional fiber-bundle matrices, and the system optical hardware design incorporates frequency-stabilized lasers, pupil-division beam combination, and a hybrid micro-macro lens for fiber-bundle imaging. Optomechanical packaging of the system ut lizes modular kinematic component positioning and active thermal control to enable simple rapid assembly. Two preliminary operational experiments are completed. In the first experiment, five stages are operated at 50 Mbits/s with 15 active inputs and outputs. The second experiment attempts to operate two stages of second-generation node arrays at 155 Mbits/s, with eight of the 15 active nodes functioning correctly along the straight switch-routing paths.


Zinc supplementation attenuates metallothionein and oxidative stress changes in kidney of streptozotocin-induced diabetic rats.
Zinc is an element that under physiological conditions preferentially binds to and is a potent inducer of metallothionein under physiological conditions. The present study was conducted to explore whether zinc supplementation morphologically and biochemically protects against diabetic nephropathy through modulation of kidney metallothionein induction and oxidative stress in streptozotocin-induced diabetic rats. Thirty-two Wistar albino male rats were equally divided into four groups. The first group was used as untreated controls and the second group was supplemented with 30 mg/kg/day zinc as zinc sulfate. The third group was treated with streptozotocin to induce diabetes and the fourth group was treated with streptozotocin and supplemented with zinc as described for group 2. The blood glucose and micro-albuminuria levels, body and kidney weights were measured during the 42-day experimental period. At the end of the experiment, the kidneys were removed from all animals from the four groups. Diabetes resulted in degenerative kidney morphological changes. The metallothionein immunoreactivity level was lower and the kidney lipid peroxidation levels were higher in the diabetes group than in the controls. The metallothionein immunoreactivity levels were higher in the tubules of the zinc-supplemented diabetic rats as compared to the non-supplemented diabetic group. The zinc and metallothionein concentrations in kidney tissue were higher in the supplemented diabetic group compared to the non-supplemented diabetes group. The activity of glutathione peroxidase did not change in any of the four groups. In conclusion, the present study shows that zinc has a protective effect against diabetic damage of kidney tissue through stimulation of metallothionein synthesis and regulation of the oxidative stress.


Feline foamy virus adversely affects feline mesenchymal stem cell culture and expansion: implications for animal model development.
Mesenchymal stem cells (MSCs) are a promising therapeutic option for various immune-mediated and inflammatory disorders due to their potent immunomodulatory and trophic properties. Naturally occurring diseases in large animal species may serve as surrogate animal models of human disease, as they may better reflect the complex genetic, environmental, and physiologic variation present in outbred populations. We work with naturally occurring diseases in large animal species to better understand how MSCs work and to facilitate optimal translation of MSC-based therapies. We are investigating the use of MSC therapy for a chronic oral inflammatory disease in cats. During our efforts to expand fat-derived feline MSCs (fMSCs), we observed that∼50% of the cell lines developed giant foamy multinucleated cells in later passages. These morphologic alterations were associated with proliferation arrest. We hypothesized that the cytopathic effects were caused by infection with a retrovirus, feline foamy virus (FFV). Using transmission electron microscopy, polymerase chain reaction, and in vitro assays, we determined that syncytial cell formation and proliferation arrest in fMSCs were caused by FFV strains that were highly homologous to previously reported FFV strains. We determined that the antiretroviral drug, tenofovir, may be used to support ex vivo expansion and salvage of FFV-infected fMSC lines. MSC lines derived from specific pathogen-free cats do not appear to be infected with FFV and may be a source of allogeneic fMSCs for clinical application. FFV infection of fMSC lines may hinder large-scale expansion of autologous MSC for therapeutic use in feline patients.


Validity assessment of the Breast Cancer Risk Reduction Health Belief scale.
: Women at increased risk of breast cancer (BC) are not widely accepting of chemopreventive interventions, and ethnic minorities are underrepresented in related trials. Furthermore, there is no validated instrument to assess the health-seeking behavior of these women with respect to these interventions. : By using constructs from the Health Belief Model, the authors developed and refined, based on pilot data, the Breast Cancer Risk Reduction Health Belief (BCRRHB) scale using a population of 265 women at increased risk of BC who were largely medically underserved, of low socioeconomic status (SES), and ethnic minorities. Construct validity was assessed using principal components analysis with oblique rotation to extract factors, and generate and interpret summary scales. Internal consistency was determined using Cronbach alpha coefficients. : Test-retest reliability for the pilot and final data was calculated to be r = 0.85. Principal components analysis yielded 16 components that explained 64% of the total variance, with communalities ranging from 0.50-0.75. Cronbach alpha coefficients for the extracted factors ranged from 0.45-0.77. : Evidence suggests that the BCRRHB yields reliable and valid data that allows for the identification of barriers and enhancing factors associated with use of breast cancer chemoprevention in the study population. These findings allow for tailoring treatment plans and intervention strategies to the individual. Future research is needed to validate the scale for use in other female populations. Cancer 2009. (c) 2009 American Cancer Society.


Muscarinic receptor blockade has differential effects on the excitability of intracortical circuits in the human motor cortex.
The aim of the present study was to investigate whether muscarinic receptor blockade with scopolamine modifies the excitability of specific cortical networks of the human motor cortex as tested with transcranial magnetic stimulation. The effects of scopolamine on the excitability of human motor cortex were investigated in four healthy subjects using transcranial magnetic stimulation before and after an intravenous dose of scopolamine (0.006 mg/kg). We measured the threshold for motor responses, amplitude of motor responses, the duration of the cortical silent period, intracortical inhibition and facilitation, and short-latency inhibition produced by somatosensory input from the hand. In addition, we evaluated the amplitude of motor responses evoked by electrical anodal stimulation, since these responses originate from direct activation of corticospinal axons in the white matter and are not sensitive to changes in cortical excitability. Scopolamine decreased the threshold to magnetic stimuli and increased the amplitude of motor responses evoked by magnetic stimulation. In contrast, motor responses evoked by electrical stimulation were unaffected by administration of scopolamine. Scopolamine also led to a highly significant reduction in the amount of short-latency inhibition produced by somatosensory input from the hand. In contrast, short-latency intracortical inhibition and facilitation were not modified by scopolamine. The differential effect of scopolamine on motor responses evoked by magnetic and electrical stimulation of the motor cortex and the selective effect on somatosensory inhibition demonstrate that muscarinic blockade modifies the excitability of specific cortical networks in the human motor cortex.


An urgent call for the environmental sustainability of health systems: A 'sextuple aim' to care for patients, costs, providers, population equity and the planet.
Health systems have a duty to protect the health and well-being of individuals and populations. Yet, healthcare contributes about 4.6% of global greenhouse gas emissions. Health systems need to question and improve established practices, assume strong environmental leadership, and aim for ambitious, sometimes radical, actions in favour of the climate. In this paper, we interrogate the suitability and feasibility of integrating the aim of 'environmental sustainability' to form the 'Sextuple Aim.' Environmental sustainability may be in tension with, but also a potential lever to meet the other cardinal aims: (1) quality and experience of patient care; (2) population health; (3) quality of work and satisfaction of healthcare providers; (4) equity and inclusion; and (5) cost reduction. We propose policy and practical avenues to help move towards the Sextuple Aim.


Premature Death Among Primary Care Patients With a History of Self-Harm.
Self-harm is a public health problem that requires a better understanding of mortality risk. We undertook a study to examine premature mortality in a nationally representative cohort of primary care patients who had harmed themselves. During 2001-2013, a total of 385 general practices in England contributed data to the Clinical Practice Research Datalink with linkage to Office for National Statistics mortality records. We identified 30,017 persons aged 15 to 64 years with a recorded episode of self-harm. We estimated the relative risks of all-cause and cause-specific natural and unnatural mortality using a comparison cohort of 600,258 individuals matched on age, sex, and general practice. We found an elevated risk of dying prematurely from any cause among the self-harm cohort, especially in the first year of follow-up (adjusted hazard ratio for that year, 3.6; 95% CI, 3.1-4.2). In particular, suicide risk was especially high during the first year (adjusted hazard ratio, 54.4; 95% CI, 34.3-86.3); although it declined sharply, it remained much higher than that in the comparison cohort. Large elevations of risk throughout the follow-up period were also observed for accidental, alcohol-related, and drug poisoning deaths. At 10 years of follow-up, cumulative incidence values were 6.5% (95% CI, 6.0%-7.1%) for all-cause mortality and 1.3% (95% CI, 1.2%-1.5%) for suicide. Primary care patients who have harmed themselves are at greatly increased risk of dying prematurely by natural and unnatural causes, and especially within a year of a first episode. These individuals visit clinicians at a relatively high frequency, which presents a clear opportunity for preventive action. Primary care patients with myriad comorbidities, including self-harming behavior, mental disorder, addictions, and physical illnesses, will require concerted, multipronged, multidisciplinary collaborative care approaches.


Structural and functional correlation in sickle cell retinopathy using spectral-domain optical coherence tomography and scanning laser ophthalmoscope microperimetry.
To correlate macular structural changes by spectral-domain optical coherence tomography (SD-OCT) with functional changes by scanning laser ophthalmoscope (SLO) microperimetry testing in patients with sickle cell hemoglobinopathies. Prospective, investigational study. Patients with electrophoretic confirmation of sickle cell hemoglobinopathies and normal subjects underwent SD-OCT and microperimetry testing with the OPKO Spectral OCT/SLO instrument. Based on SD-OCT findings, patients were grouped into those with focal macular thinning (Group A) and those without (Group B). Main outcome measure were mean retinal sensitivities measured by microperimetry and mean macular thicknesses in the 9 Early Treatment Diabetic Retinopathy Study (ETDRS)-like subfields. Thirty-seven eyes of 19 patients with sickle cell hemoglobinopathies (SS, SC, and S-thalassemia) and 34 eyes of 34 age-similar normal controls were included. Mean age and mean logMAR best-corrected visual acuity between Groups A and B were not statistically different (39.7 years vs 36.5 years, P = .64 and 0.015 vs 0.016, P = .93, respectively). Group A had significantly thinner retinas compared to Group B in the parafoveal superior (P = .019), parafoveal temporal (P < .004), parafoveal inferior (P = .003), perifoveal superior (P = .04), perifoveal temporal (P = .0005), and perifoveal inferior (P = .045) subfields. The overall mean microperimetry retinal sensitivities of Group A were significantly less than those of Group B (14.2 dB vs 16.5 dB, P = .00005). However, there was no statistical difference between Group B and controls (16.5 dB vs 16.7 dB, P = .63). Sickle cell patients with focal macular thinning present on SD-OCT have significantly decreased retinal sensitivities compared to those without focal thinning or normal controls based on mean microperimetry sensitivities, despite similar age and visual acuity. Microperimetry is a sensitive measurement of macular function in patients with sickle cell hemoglobinopathies.


Family beliefs about diet and traditional Chinese medicine for Hong Kong women with breast cancer.
To explore beliefs about diet and traditional Chinese medicine related to the breast cancer experience of Hong Kong Chinese women and their families. Interpretive phenomenology. Hong Kong, China. A purposive sample of 20 Hong Kong Chinese women diagnosed with breast cancer at various stages of the illness trajectory and at least one other family member. A semistructured, three-hour interview was translated, transcribed, and back-translated. Many women and their family members believed that diet was responsible for their cancer and recurrence. They integrated their cultural beliefs about diet and traditional Chinese medicine to manage illness symptoms and prevent recurrence. Families were anxious and confused about conflicting messages from various sources about dietary practices to promote their health and prevent recurrence. Food and diet alternatives should be discussed with the understanding that beliefs about diet and traditional Chinese medicine are embedded in culture and that many Chinese women and their families seek a combination of Eastern Chinese medicine and Western medicine strategies to manage the illness trajectory. Many Chinese families have different beliefs about food and diet and the role that food plays in managing the cancer experience. Often, Chinese people will not seek clarification if they do not understand information. If information does not fit with their predominant belief systems, families may not implement it, nor will they discuss a situation if they think the conversation will result in a relationship of conflict with healthcare providers.


Mnemonic Encoding and Cortical Organization in Parietal and Prefrontal Cortices.
Persistent activity within the frontoparietal network is consistently observed during tasks that require working memory. However, the neural circuit mechanisms underlying persistent neuronal encoding within this network remain unresolved. Here, we ask how neural circuits support persistent activity by examining population recordings from posterior parietal (PPC) and prefrontal (PFC) cortices in two male monkeys that performed spatial and motion direction-based tasks that required working memory. While spatially selective persistent activity was observed in both areas, robust selective persistent activity for motion direction was only observed in PFC. Crucially, we find that this difference between mnemonic encoding in PPC and PFC is associated with the presence of functional clustering: PPC and PFC neurons up to ∼700 μm apart preferred similar spatial locations, and PFC neurons up to ∼700 μm apart preferred similar motion directions. In contrast, motion-direction tuning similarity between nearby PPC neurons was much weaker and decayed rapidly beyond ∼200 μm. We also observed a similar association between persistent activity and functional clustering in trained recurrent neural network models embedded with a columnar topology. These results suggest that functional clustering facilitates mnemonic encoding of sensory information.SIGNIFICANCE STATEMENT Working memory refers to our ability to temporarily store and manipulate information. Numerous studies have observed that, during working memory, neurons in higher cortical areas, such as the parietal and prefrontal cortices, mnemonically encode the remembered stimulus. However, several recent studies have failed to observe mnemonic encoding during working memory, raising the question as to why mnemonic encoding is observed during some, but not all, conditions. In this study, we show that mnemonic encoding occurs when a cortical area is organized such that nearby neurons preferentially respond to the same stimulus. This result provides plausible neuronal conditions that allow for mnemonic encoding, and gives us further understanding of the brain's mechanisms that support working memory.


[Purification of Taq DNA polymerase expressed in Escherichia coli].
Taq DNA polymerase is one of the most commonly thermostable DNA polymerases in molecular biological researches, which shares its basic characters with others of the family, thereby its purifying strategy could be used not only in itself production but also in the extraction of the others as a reference. At present, the protocols reported for large scale preparation of Taq DNA are high cost, so a cheaper method was described here. In this protocol, by heat denaturation, ammonium sulfate precipitation and cation exchange chromatography of 724 resin, about 18 g powder of Na form resin could recover about 27.07 mg of Taq enzyme. The total activity and specific activity were approximately 2.2 × 10⁵ U and 8131.98 U/mg. The total yield was about 48.92% with 59.35 of purification folds. Analysis of quality of purified enzyme indicated that only one protein 94 kDa was identified against SDS-PAGE and the remnant of DNA nuclease was not detected. For PCR reaction, The amplification ability of purified Taq polymerase was not different from that of the commercially avail-able ones. This method reported in the present study is effective and low cost, making it suitable for general purification in laboratories or business production.


The role of alpha 4 beta 1 integrin in cell motility and fibronectin matrix assembly.
The alpha 4 beta 1 integrin has been suggested to play important roles in embryogenesis and pathogenesis of many diseases which involve both cell adhesion and cell migration. Previous studies using anti-alpha 4 beta 1 antibodies and fibronectin (Fn) fragments have suggested that alpha 4 beta 1 integrins may be involved in cell motility on Fn and vascular cell adhesion molecule-1 (VCAM-1). However, the cells used in these studies also express other Fn integrin receptors including alpha 5 beta 1 integrin, which is known to function in cell motility on Fn. To test whether alpha 4 beta 1 integrins mediate cell motility on Fn and VCAM-1 in the absence of alpha 5 beta 1 integrin, we expressed human alpha 4 integrin in a Chinese hamster ovary (CHO) cell line that is deficient in alpha 5 beta 1 integrin (CHO B2). The parental alpha 5 deficient CHO B2 cells were unable to adhere, spread or migrate on Fn, nor could they assemble a fibrillar Fn matrix. Expression of alpha 4 beta 1 integrin in the CHO B2 cells enabled the cells to adhere, spread and migrate on Fn and on VCAM-1 but not to assemble a fibrillar Fn matrix. The cellular processes mediated by the interaction of alpha 4 beta 1 with Fn or VCAM-1 were inhibited by the CS1 peptide derived from the major alpha 4 beta 1 binding site on Fn. These findings demonstrate that alpha 4 beta 1 integrins not only function as cell adhesion receptors but also as cell motility receptors for Fn and VCAM-1 independent of alpha 5 beta 1. Moreover, they reveal important functional differences between Fn binding integrins. The alpha 4-positive, alpha 5-negative CHO cells described in this report will be useful tools in studying the mechanism of molecular signalling during integrin mediated cellular processes.


Analysis of kinematic, kinetic and electromyographic patterns during root canal preparation with rotary and manual instruments.
This study assessed the muscular activity during root canal preparation through kinematics, kinetics, and electromyography (EMG). The operators prepared one canal with RaCe rotary instruments and another with Flexo-files. The kinematics of the major joints was reconstructed using an optoelectronic system and electromyographic responses of the flexor carpi radialis, extensor carpi radialis, brachioradialis, biceps brachii, triceps brachii, middle deltoid, and upper trapezius were recorded. The joint torques of the shoulder, elbow and wrist were calculated using inverse dynamics. In the kinematic analysis, angular movements of the wrist and elbow were classified as low risk factors for work-related musculoskeletal disorders. With respect to the shoulder, the classification was medium-risk. There was no significant difference revealed by the kinetic reports. The EMG results showed that for the middle deltoid and upper trapezius the rotary instrumentation elicited higher values. The flexor carpi radialis and extensor carpi radialis, as well as the brachioradialis showed a higher value with the manual method. The muscular recruitment for accomplishment of articular movements for root canal preparation with either the rotary or manual techniques is distinct. Nevertheless, the rotary instrument presented less difficulty in the generation of the joint torque in each articulation, thus, presenting a greater uniformity of joint torques.


Anti-Inflammatory Effects of Spirulina platensis Extract via the Modulation of Histone Deacetylases.
We previously demonstrated that the organic extract of Spirulina platensis (SPE), an edible blue-green alga, possesses potent anti-inflammatory effects. In this study, we investigated if the regulation of histone deacetylases (HDACs) play a role in the anti-inflammatory effect of SPE in macrophages. Treatment of macrophages with SPE rapidly and dose-dependently reduced HDAC2, 3, and 4 proteins which preceded decreases in their mRNA levels. Degradation of HDAC4 protein was attenuated in the presence of inhibitors of calpain proteases, lysosomal acidification, and Ca(2+)/calmodulin-dependent protein kinase II, respectively, but not a proteasome inhibitor. Acetylated histone H3 was increased in SPE-treated macrophages to a similar level as macrophages treated with a pan-HDAC inhibitor, with concomitant inhibition of inflammatory gene expression upon LPS stimulation. Knockdown of HDAC3 increased basal and LPS-induced pro-inflammatory gene expression, while HDAC4 knockdown increased basal expression of interleukin-1β (IL-1β), but attenuated LPS-induced inflammatory gene expression. Chromatin immunoprecipitation showed that SPE decreased p65 binding and H3K9/K14 acetylation at the Il-1β and tumor necrosis factor α (Tnfα) promoters. Our results suggest that SPE increased global histone H3 acetylation by facilitating HDAC protein degradation, but decreases histone H3K9/K14 acetylation and p65 binding at the promoters of Il-1β and Tnfα to exert its anti-inflammatory effect.


A helical element in the C-terminal domain of the N. plumbaginifolia F1 beta presequence is important for recognition by the mitochondrial processing peptidase.
The mitochondrial processing peptidase (MPP) in lower eucaryots and mammals is a matrix enzyme, whereas MPP in plants constitutes an integral part of the bc1 complex of the respiratory chain. The isolated spinach leaf bc1 complex catalyzes cleavage of the precursor of Nicotiana plumbaginifolia F1 beta subunit of the ATP synthase, resulting in a production of mature protein and a presequence that consists of 54 amino acids. A synthetic peptide derived from the C-terminal part of the presequence, containing 17 amino acids with a helical structural element, p-F1 beta(38-54), was an efficient inhibitor of the processing, whereas a peptide derived from the N-terminal part of the presequence, p-F1 beta(1-18), was much less effective. ATIII, a helical peptide derived from antithrombin III, was not recognized by MPP. Synthetic peptides corresponding to 4, 6, and 11 amino acids of the C terminus of the presequence, p-F1 beta(51-54), p-F1 beta(49-54), and p-F1 beta(44-54) were almost completely inert. Competition studies show that MPP recognizes the C-terminal domain of the presequence rather than the N-terminal domain. Furthermore, the alpha-helical element of the C-terminal domain is shown to be required for the recognition event.


Polyphosphate blocks tumour metastasis via anti-angiogenic activity.
PolyP (inorganic polyphosphate) is a linear polymer of many tens or hundreds of orthophosphate residues found in a wide range of organisms, including bacteria, fungi, insects, plants and vertebrates. Despite its wide distribution in mammalian tissues and plasma, the biological functions of polyP on tumour metastasis and angiogenesis have not been previously examined. In the present study, we have shown that polyP effectively blocked in vivo pulmonary metastasis of B16BL6 cells by suppression of neovascularization, whereas it did not affect proliferation or adhesion to extracellular matrix proteins. PolyP not only inhibited bFGF (basic fibroblast growth factor)-induced proliferation and ERK (extracellular-signal-regulated kinase)/p38 MAPK (mitogen-activated protein kinase) activation of human endothelial cells, but also blocked the binding of bFGF to its cognate cell-surface receptor. Furthermore, polyP inhibited bFGF-induced in vitro and in vivo angiogenesis, suggesting that polyP possesses an anti-angiogenic activity. Since neovascularization is essential for tumour metastasis, our present findings clearly indicate that polyP has an in vivo anti-metastatic activity via its anti-angiogenic activity. Taken together with the fact that angiogenesis occurs under various normal and pathological conditions, our observations suggest that endogenous polyP may play a critical role during embryonic development, wound healing and inflammation, as well as in the progress of pathological diseases such as rheumatoid arthritis and cancer.


Postanalyses of an optical multilayer interference filter using numerical reverse synthesis and Rutherford backscattering spectrometry.
Post nondestructive analyses of an all-dielectric multilayer Fabry-Perot interference filter developed through a reactive electron beam deposition process have been carried out through numerical reverse engineering of transmission spectra, Rutherford backscattering spectroscopy and quartz crystal monitoring data to derive multilayer geometry, deposited layer thicknesses, densities, refractive indices, compositions, and stoichiometry. These techniques are collectively used to fulfill the missing links with complementary and some supplementary information to inverse synthesize the multilayer geometry. During this investigation it is distinctly understood that the factors associated with real-time deposition have significantly influenced the microscopic parameters, namely, the densities and refractive indices of TiO2 and SiO2 layers. This in turn influenced the layers' geometric (physical) thicknesses during automated quarter-wave optical layer monitoring and consequently affected the experimental spectral characteristics. The role of oxygen has been observed to be significant in controlling the mass densities of these refractory oxide layers. It is further noticed that the layer density values have been significantly perturbed whether the associated TiO2 or SiO2 oxide dielectric films are substoichiometric (oxygen-deficient), stoichiometric, or superstoichiometric (oxygen-enriched).


A single member of the Plasmodium falciparum var multigene family determines cytoadhesion to the placental receptor chondroitin sulphate A.
In high-transmission regions, protective clinical immunity to Plasmodium falciparum develops during the early years of life, limiting serious complications of malaria in young children. Pregnant women are an exception and are especially susceptible to severe P. falciparum infections resulting from the massive adhesion of parasitized erythrocytes to chondroitin sulphate A (CSA) present on placental syncytiotrophoblasts. Epidemiological studies strongly support the feasibility of an intervention strategy to protect pregnant women from disease. However, different parasite molecules have been associated with adhesion to CSA. In this work, we show that disruption of the var2csa gene of P. falciparum results in the inability of parasites to recover the CSA-binding phenotype. This gene is a member of the var multigene family and was previously shown to be composed of domains that mediate binding to CSA. Our results show the central role of var2CSA in CSA adhesion and support var2CSA as a leading vaccine candidate aimed at protecting pregnant women and their fetuses.


Silicification of peptide-coated silver nanoparticles--A Biomimetic soft chemistry approach toward chiral hybrid core-shell materials.
Silica and silver nanoparticles are relevant materials for new applications in optics, medicine, and analytical chemistry. We have previously reported the synthesis of pH responsive, peptide-templated, chiral silver nanoparticles. The current report shows that peptide-stabilized nanoparticles can easily be coated with a silica shell by exploiting the ability of the peptide coating to hydrolyze silica precursors such as TEOS or TMOS. The resulting silica layer protects the nanoparticles from chemical etching, allows their inclusion in other materials, and renders them biocompatible. Using electron and atomic force microscopy, we show that the silica shell thickness and the particle aggregation can be controlled simply by the reaction time. Small-angle X ray scattering confirms the Ag/peptide@silica core-shell structure. UV-vis and circular dichroism spectroscopy prove the conservation of the silver nanoparticle chirality upon silicification. Biological tests show that the biocompatibility in simple bacterial systems is significantly improved once a silica layer is deposited on the silver particles.


ProRata: A quantitative proteomics program for accurate protein abundance ratio estimation with confidence interval evaluation.
A profile likelihood algorithm is proposed for quantitative shotgun proteomics to infer the abundance ratios of proteins from the abundance ratios of isotopically labeled peptides derived from proteolysis. Previously, we have shown that the estimation variability and bias of peptide abundance ratios can be predicted from their profile signal-to-noise ratios. Given multiple quantified peptides for a protein, the profile likelihood algorithm probabilistically weighs the peptide abundance ratios by their inferred estimation variability, accounts for their expected estimation bias, and suppresses contribution from outliers. This algorithm yields maximum likelihood point estimation and profile likelihood confidence interval estimation of protein abundance ratios. This point estimator is more accurate than an estimator based on the average of peptide abundance ratios. The confidence interval estimation provides an "error bar" for each protein abundance ratio that reflects its estimation precision and statistical uncertainty. The accuracy of the point estimation and the precision and confidence level of the interval estimation were benchmarked with standard mixtures of isotopically labeled proteomes. The profile likelihood algorithm was integrated into a quantitative proteomics program, called ProRata, freely available at www.MSProRata.org.


Effects of altered auditory feedback across effector systems: production of melodies by keyboard and singing.
We report an experiment that tested whether effects of altered auditory feedback (AAF) during piano performance differ from its effects during singing. These effector systems differ with respect to the mapping between motor gestures and pitch content of auditory feedback. Whereas this action-effect mapping is highly reliable during phonation in any vocal motor task (singing or speaking), mapping between finger movements and pitch occurs only in limited situations, such as piano playing. Effects of AAF in both tasks replicated results previously found for keyboard performance (Pfordresher, 2003), in that asynchronous (delayed) feedback slowed timing whereas alterations to feedback pitch increased error rates, and the effect of asynchronous feedback was similar in magnitude across tasks. However, manipulations of feedback pitch had larger effects on singing than on keyboard production, suggesting effector-specific differences in sensitivity to action-effect mapping with respect to feedback content. These results support the view that disruption from AAF is based on abstract, effector independent, response-effect associations but that the strength of associations differs across effector systems.


Approaches to semi-synthetic minimal cells: a review.
Following is a synthetic review on the minimal living cell, defined as an artificial or a semi-artificial cell having the minimal and sufficient number of components to be considered alive. We describe concepts and experiments based on these constructions, and we point out that an operational definition of minimal cell does not define a single species, but rather a broad family of interrelated cell-like structures. The relevance of these researches, considering that the minimal cell should also correspond to the early simple cell in the origin of life and early evolution, is also explained. In addition, we present detailed data in relation to minimal genome, with observations cited by several authors who agree on setting the theoretical full-fledged minimal genome to a figure between 200 and 300 genes. However, further theoretical assumptions may significantly reduce this number (i.e. by eliminating ribosomal proteins and by limiting DNA and RNA polymerases to only a few, less specific molecular species). Generally, the experimental approach to minimal cells consists in utilizing liposomes as cell models and in filling them with genes/enzymes corresponding to minimal cellular functions. To date, a few research groups have successfully induced the expression of single proteins, such as the green fluorescence protein, inside liposomes. Here, different approaches are described and compared. Present constructs are still rather far from the minimal cell, and experimental as well as theoretical difficulties opposing further reduction of complexity are discussed. While most of these minimal cell constructions may represent relatively poor imitations of a modern full-fledged cell, further studies will begin precisely from these constructs. In conclusion, we give a brief outline of the next possible steps on the road map to the minimal cell.


Variability in conditioned pain modulation predicts response to NSAID treatment in patients with knee osteoarthritis.
Patients with painful knee osteoarthritis (OA) demonstrate hyperalgesia and altered pain-modulatory responses. While some prior work has demonstrated cross-sectional associations between laboratory and clinical pain measures, it is unknown whether individual variability in quantitative sensory testing (QST) responses at baseline can prospectively predict analgesic treatment responses. Patients with knee OA (n = 35) were compared on QST responses to a demographically-matched pain-free control group (n = 39), after which patients completed a month-long treatment study of diclofenac sodium topical gel (1 %), applied up to 4 times daily. OA patients demonstrated reduced pain thresholds at multiple anatomic sites, as well as reduced conditioned pain modulation (CPM) and enhanced temporal summation of pain. The most pain-sensitive patients tended to report the most intense and neuropathic OA pain. Following diclofenac treatment, the knee OA cohort showed a roughly 30 % improvement in pain, regardless of the presence or absence of neuropathic symptoms. Baseline CPM scores, an index of endogenous pain-inhibitory capacity, were prospectively associated with treatment-related changes in clinical pain. Specifically, participants with higher CPM at baseline (i.e., better functioning endogenous pain-inhibitory systems) showed more reduction in pain at the end of treatment (p < .05). These results support prior findings of amplified pain sensitivity and reduced pain-inhibition in OA patients. Moreover, the moderate to strong associations between laboratory-based measures of pain sensitivity and indices of clinical pain highlight the clinical relevance of QST in this sample. Finally, the prospective association between CPM and diclofenac response suggests that QST-based phenotyping may have utility in explaining inter-patient variability in long-term analgesic treatment outcomes. ClinicalTrials.Gov Identifier: NCT01383954 . Registered June 22, 2011.


Pathogenic Delivery: The Biological Roles of Cryptococcal Extracellular Vesicles.
Extracellular vesicles (EVs) are produced by all domains of life. In fungi, these structures were first described in Cryptococcus neoformans and, since then, they were characterized in several pathogenic and non-pathogenic fungal species. Cryptococcal EVs participate in the export of virulence factors that directly impact the Cryptococcus-host interaction. Our knowledge of the biogenesis and pathogenic roles of Cryptococcus EVs is still limited, but recent methodological and scientific advances have improved our understanding of how cryptococcal EVs participate in both physiological and pathogenic events. In this review, we will discuss the importance of cryptococcal EVs, including early historical studies suggesting their existence in Cryptococcus, their putative mechanisms of biogenesis, methods of isolation, and possible roles in the interaction with host cells.


Validation of the modified Sgarbossa criteria for acute coronary occlusion in the setting of left bundle branch block: A retrospective case-control study.
The modified Sgarbossa criteria were proposed in a derivation study to be superior to the original criteria for diagnosing acute coronary occlusion (ACO) in left bundle branch block (LBBB). The new rule replaces the third criterion (5 mm of excessively discordant ST elevation [STE]) with a proportion (at least 1 mm STE and STE/S wave ≤-0.25). We sought to validate the modified criteria. This retrospective case-control study was performed by chart review in 2 tertiary care center emergency departments (EDs) and 1 regional referral center. A billing database was used at 1 site to identify all ED patients with LBBB and ischemic symptoms between May 2009 and June 2012. In addition, all 3 sites identified LBBB ACO patients who underwent emergent catheterization. We measured QRS amplitude and J-point deviation in all leads, blinded to outcomes. Acute coronary occlusion was determined by angiographic findings and cardiac biomarker levels, which were collected blinded to electrocardiograms. Diagnostic statistics of each rule were calculated and compared using McNemar's test. Our consecutive cohort search identified 258 patients: 9 had ACO, and 249 were controls. Among the 3 sites, an additional 36 cases of ACO were identified, for a total of 45 ACO cases and 249 controls. The modified criteria were significantly more sensitive than the original weighted criteria (80% vs 49%, P < .001) and unweighted criteria (80% vs 56%, P < .001). Specificity of the modified criteria was not statistically different from the original weighted criteria (99% vs 100%, P = .5) but was significantly greater than the original unweighted criteria (99% vs 94%, P = .004). The modified Sgarbossa criteria were superior to the original criteria for identifying ACO in LBBB.


Peripheral blood DNA methylation profiles are indicative of head and neck squamous cell carcinoma: an epigenome-wide association study.
Head and neck cancer accounts for an estimated 47,560 new cases and 11,480 deaths annually in the United States, the majority of which are squamous cell carcinomas (HNSCC). The overall 5 year survival is approximately 60% and declines with increasing stage at diagnosis, indicating a need for non-invasive tests that facilitate the detection of early disease. DNA methylation is a stable epigenetic modification that is amenable to measurement and readily available in peripheral blood. We used a semi-supervised recursively partitioned mixture model (SS-RPMM) approach to identify novel blood DNA methylation markers of HNSCC using genome-wide methylation array data for peripheral blood samples from 92 HNSCC cases and 92 cancer-free control subjects. To assess the performance of the resultant markers, we constructed receiver operating characteristic (ROC) curves and calculated the corresponding area under the curve (AUC). Cases and controls were best differentiated by a methylation profile of six CpG loci (associated with FGD4, SERPINF1, WDR39, IL27, HYAL2 and PLEKHA6), with an AUC of 0.73 (95% CI: 0.62-0.82). After adjustment for subject age, gender, smoking, alcohol consumption and HPV16 serostatus, the AUC increased to 0.85 (95% CI: 0.76-0.92). We have identified a novel blood-based methylation profile that is indicative of HNSCC with a high degree of accuracy. This profile demonstrates the potential of DNA methylation measured in blood for development of non-invasive applications for detection of head and neck cancer.


Disentangling the Impact of Chronic Kidney Disease, Anemia, and Mobility Limitation on Mortality in Older Patients Discharged From Hospital.
Chronic kidney disease (CKD), anemia, and mobility limitation are important predictors of mortality. We aimed at investigating the interactions between estimated glomerular filtration rate (eGFR), anemia, and physical performance on 1-year mortality in older patients discharged from acute care hospitals. Four hundred and eighty seven patients enrolled in a multicenter, prospective observational study were included in the analysis. eGFR was estimated by the Berlin Initiative Study 1 equation. Anemia was defined on the basis of hemoglobin values. Mobility limitation was rated by the Short Physical Performance Battery (SPPB). Covariates included demographics, nutritional status, cognitive performance, and comorbidity. The outcome of the study was mortality over 1-year follow-up. Interactions among study variables were investigated by survival tree analysis. eGFR < 30 mL/min/1.73 m(2), anemia, and SPPB = 0-4 were significantly associated with mortality, as were hypoalbuminemia and cognitive impairment. Survival tree analysis showed that compared to patients with SPPB ≥ 4 and eGFR ≥ 46.7 mL/min/1.73 m(2) (ie, patients with the least mortality), patients with SPPB < 4 and hemoglobin < 12.2 g/dL had the highest risk of mortality [hazard ratio (HR) = 28.9, 95%CI 10.3-81.2]. Patients with SPPB ≥ 4 and eGFR < 46.7 mL/min/1.73 m(2) and those with SPPB > 4, hemoglobin ≥ 12.2g/dL, and eGFR ≥ 58.6 mL/min/1.73 m(2) had intermediate risk (HR = 6.58, 95%CI = 2.15-20.2, and HR = 15.11, 95%CI=4.42-51.7, respectively). Having SPPB < 4, hemoglobin ≥ 12.2 g/dL, and eGFR<58.6 mL/min/l.73 m(2) was not significantly associated with increased mortality (HR = 2.95, 95%CI = 0.74-11.8). Interactions among eGFR, anemia, and mobility limitation define different profiles of risk in older patients discharged from acute care hospitals, which deserve to be considered to identify patients needing special care and careful follow-up after discharge.


The development of newborn object recognition in fast and slow visual worlds.
Object recognition is central to perception and cognition. Yet relatively little is known about the environmental factors that cause invariant object recognition to emerge in the newborn brain. Is this ability a hardwired property of vision? Or does the development of invariant object recognition require experience with a particular kind of visual environment? Here, we used a high-throughput controlled-rearing method to examine whether newborn chicks (Gallus gallus) require visual experience with slowly changing objects to develop invariant object recognition abilities. When newborn chicks were raised with a slowly rotating virtual object, the chicks built invariant object representations that generalized across novel viewpoints and rotation speeds. In contrast, when newborn chicks were raised with a virtual object that rotated more quickly, the chicks built viewpoint-specific object representations that failed to generalize to novel viewpoints and rotation speeds. Moreover, there was a direct relationship between the speed of the object and the amount of invariance in the chick's object representation. Thus, visual experience with slowly changing objects plays a critical role in the development of invariant object recognition. These results indicate that invariant object recognition is not a hardwired property of vision, but is learned rapidly when newborns encounter a slowly changing visual world.


Coordination as a best practice from the polio eradication initiative: Experiences from five member states in the African region of the World Health Organization.
As part of the efforts to eradicate polioviruses in the African Region, structures were put in place to ensure coordinated mobilization and deployment of resources within the framework of the global polio eradication initiative (PEI). The successes of these structures made them not only attractive to other public health interventions, but also caused them to be deployed to the response efforts of other diseases interventions, without any systematic documentation. This article documents the contributions of PEI coordination units to other public health interventions in the African Region of World Health Organization METHODS: We reviewed the contributions of PEI coordination units to other public health interventions in five countries in the African Region. The analysis identified significant involvement of PEI coordination structures in the implementation of routine immunization programs in all the countries analyzed. Similarly, maternal and child health programs were planned, implemented, monitored and evaluation the Inter-Agency Coordination Committees of the PEI programs in the different countries. The hubs system used in PEI in Chad facilitated the efficient coordination of resources for immunization and other public health interventions in Chad. Similarly, in the Democratic Republic of Congo PEI led coordination activities benefited other public health programs like disease control and the national nutrition program, the national malaria control program, and the tuberculosis control program. In Nigeria, the polio Expert Review Committee effectively deployed the Emergency Operation Center for the implementation of prioritized strategies and activities of the National Polio Eradication Emergency Plan, and it was utilized in the response to Ebola Virus Disease outbreak in the country. The PEI-led coordination systems are thus recognized as having made significant contribution to the coordination and delivery of other public health interventions in the African Region.


Economic burden of melanoma in the elderly population: population-based analysis of the Surveillance, Epidemiology, and End Results (SEER)--Medicare data.
To assess health care resources consumed by melanoma in the population 65 years or older, a group with comparatively poor outcomes. Database analysis. The Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked population-based database for fiscal years 1991 through 1996. A total of 1858 subjects with pathological confirmation of melanoma. Resource consumption was examined by stage and treatment phase. Outcomes were measured in monthly charges obtained from the data set and costs were estimated by application of cost to charge ratios. Annual resource consumption by melanoma in patients 65 years or older in the United States was also estimated by incorporation of published SEER cancer statistics. Average monthly, per-patient melanoma charges were $2194 during the initial 4 months of treatment; they dropped by more than half to $902 during the interim phase, which varied in length depending on survival. Monthly charges increased to $3933 during the terminal 6 months of treatment. The estimated annual charge of treating melanoma in the population 65 years or older was $390 million. By using cost to charge ratios, we found the annual cost of melanoma to be up to $249 million and the per-patient lifetime costs to be $28 210 from the time of diagnosis to the time of death. Melanoma care presents a significant economic burden in the elderly population, particularly in late-stage disease. If effective, prevention and early detection efforts may reduce the economic burden.


What Is a Host? Attributes of Individual Susceptibility.
In every epidemic some individuals become sick and some may die, whereas others recover from illness and still others show no signs or symptoms of disease. These differences highlight a fundamental question of microbial pathogenesis: why are some individuals susceptible to infectious diseases while others who acquire the same microbe remain well? For most of human history, the answer assumed the hand of providence. With the advent of the germ theory of disease, the focus on disease causality became the microbe, but this did not explain how there can be different outcomes of infection in different individuals with the same microbe. Here we examine the attributes of susceptibility in the context of the "damage-response framework" of microbial pathogenesis. We identify 11 attributes that, although not independent, are sufficiently distinct to be considered separately: microbiome, inoculum, sex, temperature, environment, age, chance, history, immunity, nutrition, and genetics. We use the first letter of each to create the mnemonic MISTEACHING, underscoring the need for caution in accepting dogma and attributing disease causality to any single factor. For both populations and individuals, variations in the attributes that assemble into MISTEACHING can create an enormity of combinations that can in turn translate into different outcomes of host-microbe encounters. Combinatorial diversity among the 11 attributes makes identifying "signatures" of susceptibility possible. However, with their inevitable uncertainties and propensity to change, there may still be a low likelihood for prediction with regard to individual host-microbe interactions, although probabilistic prediction may be possible.


Online Support and Intervention (OSI) for child anxiety: a case series within routine clinical practice.
Online treatments for child anxiety offer a potentially cost-effective and non-stigmatizing means to widen access to evidence-based treatments and meet the increasing demand on services; however, uptake in routine clinical practice remains a challenge. This study conducted an initial evaluation of the clinical effectiveness, feasibility and acceptability of OSI (Online Support and Intervention for child anxiety) within clinical practice. OSI is a co-designed online therapist-supported, parent-led CBT treatment for pre-adolescent children with anxiety problems. This case series was part of routine service evaluation in a clinic in England where families were offered OSI to treat a primary anxiety difficulty among 7- to 12-year-old children; 24 families were offered OSI, and 23 took it up. Measures of anxiety symptomatology, functional impairment and progress towards therapeutic goals were taken at pre-treatment, post-treatment and 4-week follow-up. Treatment satisfaction and engagement were also measured throughout the intervention. Mean anxiety symptoms significantly improved to below the clinical cut-off post-treatment, with further reduction at follow-up. Functional impairment also significantly improved and significant progress was made towards treatment goals. The majority of children showed reliable change in anxiety symptoms and reliable recovery by follow-up, and were discharged without needing further treatment for anxiety. Uptake, adherence and engagement in OSI were excellent, and parents reported high levels of satisfaction with the treatment. We have provided initial evidence that OSI is feasible, acceptable to families, and appears to be associated with good outcomes within routine clinical practice.


Edema: diagnosis and management.
Edema is an accumulation of fluid in the interstitial space that occurs as the capillary filtration exceeds the limits of lymphatic drainage, producing noticeable clinical signs and symptoms. The rapid development of generalized pitting edema associated with systemic disease requires timely diagnosis and management. The chronic accumulation of edema in one or both lower extremities often indicates venous insufficiency, especially in the presence of dependent edema and hemosiderin deposition. Skin care is crucial in preventing skin breakdown and venous ulcers. Eczematous (stasis) dermatitis can be managed with emollients and topical steroid creams. Patients who have had deep venous thrombosis should wear compression stockings to prevent postthrombotic syndrome. If clinical suspicion for deep venous thrombosis remains high after negative results are noted on duplex ultrasonography, further investigation may include magnetic resonance venography to rule out pelvic or thigh proximal venous thrombosis or compression. Obstructive sleep apnea may cause bilateral leg edema even in the absence of pulmonary hypertension. Brawny, nonpitting skin with edema characterizes lymphedema, which can present in one or both lower extremities. Possible secondary causes of lymphedema include tumor, trauma, previous pelvic surgery, inguinal lymphadenectomy, and previous radiation therapy. Use of pneumatic compression devices or compression stockings may be helpful in these cases.


Transcriptomic analysis identifies gene networks regulated by estrogen receptor α (ERα) and ERβ that control distinct effects of different botanical estrogens.
The estrogen receptors (ERs) ERα and ERβ mediate the actions of endogenous estrogens as well as those of botanical estrogens (BEs) present in plants. BEs are ingested in the diet and also widely consumed by postmenopausal women as dietary supplements, often as a substitute for the loss of endogenous estrogens at menopause. However, their activities and efficacies, and similarities and differences in gene expression programs with respect to endogenous estrogens such as estradiol (E2) are not fully understood. Because gene expression patterns underlie and control the broad physiological effects of estrogens, we have investigated and compared the gene networks that are regulated by different BEs and by E2. Our aim was to determine if the soy and licorice BEs control similar or different gene expression programs and to compare their gene regulations with that of E2. Gene expression was examined by RNA-Seq in human breast cancer (MCF7) cells treated with control vehicle, BE or E2. These cells contained three different complements of ERs, ERα only, ERα+ERβ, or ERβ only, reflecting the different ratios of these two receptors in different human breast cancers and in different estrogen target cells. Using principal component, hierarchical clustering, and gene ontology and interactome analyses, we found that BEs regulated many of the same genes as did E2. The genes regulated by each BE, however, were somewhat different from one another, with some genes being regulated uniquely by each compound. The overlap with E2 in regulated genes was greatest for the soy isoflavones genistein and S-equol, while the greatest difference from E2 in gene expression pattern was observed for the licorice root BE liquiritigenin. The gene expression pattern of each ligand depended greatly on the cell background of ERs present. Despite similarities in gene expression pattern with E2, the BEs were generally less stimulatory of genes promoting proliferation and were more pro-apoptotic in their gene regulations than E2. The distinctive patterns of gene regulation by the individual BEs and E2 may underlie differences in the activities of these soy and licorice-derived BEs in estrogen target cells containing different levels of the two ERs.


Replay of cortical spiking sequences during human memory retrieval.
Episodic memory retrieval is thought to rely on the replay of past experiences, yet it remains unknown how human single-unit activity is temporally organized during episodic memory encoding and retrieval. We found that ripple oscillations in the human cortex reflect underlying bursts of single-unit spiking activity that are organized into memory-specific sequences. Spiking sequences occurred repeatedly during memory formation and were replayed during successful memory retrieval, and this replay was associated with ripples in the medial temporal lobe. Together, these data demonstrate that human episodic memory is encoded by specific sequences of neural activity and that memory recall involves reinstating this temporal order of activity.


Assessment of tumour hypoxia for prediction of response to therapy and cancer prognosis.
Tumour cells exploit both genetic and adaptive means to survive and proliferate in hypoxic microenvironments, resulting in the outgrowth of more aggressive tumour cell clones. Direct measurements of tumour oxygenation, and surrogate markers of the hypoxic response in tumours (for instance, hypoxia inducible factor-1alpha, carbonic anhydrase 9 and glucose transporter-1) are well-established prognostic markers in solid cancers. However, individual markers do not fully capture the complex, dynamic and heterogeneous hypoxic response in cancer. To overcome this, expression profiling has been employed to identify hypoxia signatures in cohorts or models of human cancer. Several of these hypoxia signatures have demonstrated prognostic significance in independent cancer datasets. Nevertheless, individual hypoxia markers have been shown to predict the benefit from hypoxia-modifying or anti-angiogenic therapies. This review aims to discuss the clinical impact of translational work on hypoxia markers and to explore future directions for research in this area.


Calcium accumulation and enzymatic activities of subcellular fractions from aortas and ventricles of genetically hypertensive rats.
Subcellular fractions were obtained from aortas and ventricles of 6-month-old spontaneously hypertensive and normotensive Wistar rats by the use of differential and sucrose density gradient centrifugation. These preparations were studied to determine what alterations in calcium accumulation and enzymatic activities might be associated with hypertension. The total amount of calcium accumulation (in the presence of ATP and 17 muM free calcium) by the plasma membrane-enriched fraction from hypertensive rat aortas significantly less than that from normotensive rats (11.3 +/- 0.4 vs 16.2 +/- 1.6 mumol of calcium/g of protein, n = 8). In contrast the specific activities of the plasma membrane marker enzymes, 5'-nucleotidase and phosphodiesterase I, were 80% and 40% greater, respectively, in the hypertensive than in the normotensive fractions. On the other hand, various fractions from ventricles of the two types of rats were generally similar in enzyme activities and calcium accumulation. The decreased rate of relaxation of aortas from spontaneously hypertensive rats may be caused by the decreased rate of calcium transport demonstrated in this study.


Myocardial infarction in relation to mercury and fatty acids from fish: a risk-benefit analysis based on pooled Finnish and Swedish data in men.
Exposure to methylmercury from fish has been associated with increased risk of myocardial infarction (MI) in some studies. At the same time, marine n-3 (omega-3) PUFAs are an inherent constituent of fish and are regarded as beneficial. To our knowledge, no risk-benefit model on the basis of data on methylmercury, PUFA, and MI risk has yet been presented. The objective of this study was to describe how exposure to both marine n-3 PUFAs and methylmercury relates to MI risk by using data from Finland and Sweden. We used matched case-control sets from Sweden and Finland that were nested in population-based, prospective cohort studies. We included 361 men with MI from Sweden and 211 men with MI from Finland. MI risk was estimated in a logistic regression model with the amount of mercury in hair (hair-Hg) and concentrations of n-3 PUFAs (EPA and DHA) in serum (S-PUFA) as independent variables. The median hair-Hg was 0.57 μg/g in Swedish and 1.32 μg/g in Finnish control subjects, whereas the percentage of S-PUFA was 4.21% and 3.83%, respectively. In combined analysis, hair-Hg was associated with higher (P = 0.005) and S-PUFA with lower (P = 0.011) MI risk. Our model indicated that even a small change in fish consumption (ie, by increasing S-PUFA by 1%) would prevent 7% of MIs, despite a small increase in mercury exposure. However, at a high hair-Hg, the modeled beneficial effect of PUFA on MI risk was counteracted by methylmercury. Exposure to methylmercury was associated with increased risk of MI, and higher S-PUFA concentrations were associated with decreased risk of MI. Thus, MI risk may be reduced by the consumption of fish high in PUFAs and low in methylmercury.


Cerebral control of eye movements. I. The relationship between cerebral lesion sites and smooth pursuit deficits.
We investigated smooth pursuit eye movements in 72 patients with focal cerebral lesions using a sinusoidal pursuit task at multiple target frequencies and amplitudes. Twenty patients had normal pursuit gain and symmetry at all target frequencies, 12 had strictly ipsilesional pursuit deficit, 19 had symmetric bi-directional pursuit deficit, 18 had asymmetric bi-directional pursuit deficit (the deficit being more severe on the side of the lesion) and three had more severe contra-directional deficit. Normal pursuit gain was found in patients whose lesions were limited to the frontal, temporal and occipital poles, or the primary somaesthetic areas. Predominant ipsilesional pursuit deficit occurred in a long band of lesion overlap areas that run from the V5 occipito-temporal areas posteriorly, through the internal sagittal stratum, the posterior and anterior limbs of the internal capsule with adjacent striatum, to the dorsomedial frontal cortex anteriorly. Symmetric bi-directional deficit was associated with lesions involving the regions of the cortico-limbic-reticular network for directed attention, including the frontal eye fields, the posterior parietal cortex and the thalamus. Asymmetric bi-directional deficit resulted from lesions that penetrated into the underlying/adjacent white matter from the frontal eye field, posterior parietal cortex and thalamus. Varying combinations of lesions in the areas associated with uni-directional and symmetric bi-directional deficits produced a graded continuum from strict ipsi-directional pursuit deficit, through asymmetric bi-directional deficit, to symmetric bi-directional deficit. The striatum was identified as the area of lesion overlap in patients with large phase errors. Patients with lesions involving the right posterior parietal cortex and/or right dorsolateral frontal cortex had significantly more severe impairments than their counterparts with left-sided lesions. All pursuit deficits were more pronounced at high frequencies.


Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs.
Long transcripts that do not encode protein have only rarely been the subject of experimental scrutiny. Presumably, this is owing to the current lack of evidence of their functionality, thereby leaving an impression that, instead, they represent "transcriptional noise." Here, we describe an analysis of 3122 long and full-length, noncoding RNAs ("macroRNAs") from the mouse, and compare their sequences and their promoters with orthologous sequence from human and from rat. We considered three independent signatures of purifying selection related to substitutions, sequence insertions and deletions, and splicing. We find that the evolution of the set of noncoding RNAs is not consistent with neutralist explanations. Rather, our results indicate that purifying selection has acted on the macroRNAs' promoters, primary sequence, and consensus splice site motifs. Promoters have experienced the greatest elimination of nucleotide substitutions, insertions, and deletions. The proportion of conserved sequence (4.1%-5.5%) in these macroRNAs is comparable to the density of exons within protein-coding transcripts (5.2%). These macroRNAs, taken together, thus possess the imprint of purifying selection, thereby indicating their functionality. Our findings should now provide an incentive for the experimental investigation of these macroRNAs' functions.


Quorum sensing contributes to activated IgM-secreting B cell homeostasis.
Maintenance of plasma IgM levels is critical for immune system function and homeostasis in humans and mice. However, the mechanisms that control homeostasis of the activated IgM-secreting B cells are unknown. After adoptive transfer into immune-deficient hosts, B lymphocytes expand poorly, but fully reconstitute the pool of natural IgM-secreting cells and circulating IgM levels. By using sequential cell transfers and B cell populations from several mutant mice, we were able to identify novel mechanisms regulating the size of the IgM-secreting B cell pool. Contrary to previous mechanisms described regulating homeostasis, which involve competition for the same niche by cells having overlapping survival requirements, homeostasis of the innate IgM-secreting B cell pool is also achieved when B cell populations are able to monitor the number of activated B cells by detecting their secreted products. Notably, B cell populations are able to assess the density of activated B cells by sensing their secreted IgG. This process involves the FcγRIIB, a low-affinity IgG receptor that is expressed on B cells and acts as a negative regulator of B cell activation, and its intracellular effector the inositol phosphatase SHIP. As a result of the engagement of this inhibitory pathway, the number of activated IgM-secreting B cells is kept under control. We hypothesize that malfunction of this quorum-sensing mechanism may lead to uncontrolled B cell activation and autoimmunity.


Etiologies for seizures around the time of vaccination.
This study was an assessment of the incidence, course, and etiology of epilepsy with vaccination-related seizure onset in a population-based cohort of children. The medical data of 990 children with seizures after vaccination in the first 2 years of life, reported to the National Institute for Public Health and Environment in the Netherlands in 1997 through 2006, were reviewed. Follow-up data were obtained of children who were subsequently diagnosed with epilepsy and had had seizure onset within 24 hours after administration of an inactivated vaccine or 5 to 12 days after a live attenuated vaccine. Follow-up was available for 23 of 26 children (median age: 10.6 years) with epilepsy onset after vaccination. Twelve children developed epileptic encephalopathy, 8 had benign epilepsy, and 3 had encephalopathy before seizure onset. Underlying causes were identified in 15 children (65%) and included SCN1A-related Dravet syndrome (formerly severe myoclonic epilepsy of infancy) or genetic epilepsy with febrile seizures plus syndrome (n = 8 and n = 1, respectively), a protocadherin 19 mutation, a 1qter microdeletion, neuronal migration disorders (n = 2), and other monogenic familial epilepsy (n = 2). Our results suggest that in most cases, genetic or structural defects are the underlying cause of epilepsy with onset after vaccination, including both cases with preexistent encephalopathy or benign epilepsy with good outcome. These results have significant added value in counseling of parents of children with vaccination-related first seizures, and they might help to support public faith in vaccination programs.


"Under My Umbrella": the housing experiences of HIV positive parents who live with and care for their children in Ontario.
Positive Spaces, Healthy Places (PSHP) is the first longitudinal community-based research (CBR) initiative in Canada to examine housing stability and its relationship to health related quality of life (HRQOL) for people living with of HIV/AIDS (PHAs). As part of our mixed method data collection strategy in-depth, semi-structured interviews were conducted with 50 PHAs across Ontario to provide a deeper understanding of the impact that housing instability has on their mental and physical health. Emerging from the qualitative interviews were the unique issues and concerns that were reported by parents who live with and care for their children. These parents face dire housing, economic and social challenges that are associated with significant risks for poor health outcomes. Poor housing conditions, unsafe neighborhoods, barriers to supports for themselves and their children, HIV related stigma, discrimination, racism, and poverty have been identified by these families as being among their most pressing concerns. This results in increased stress and anxiety that has a negative impact on the mental health of HIV positive parents. In order to more effectively support HIV positive parents and their children, health and social service practices and policies must respond to the unique challenges that face these families.


Use of Radiology Procedure Codes in Health Care: The Need for Standardization and Structure.
Radiology procedure codes are a fundamental part of most radiology workflows, such as ordering, scheduling, billing, and image interpretation. Nonstandardized unstructured procedure codes have typically been used in radiology departments. Such codes may be sufficient for specific purposes, but they offer limited support for interoperability. As radiology workflows and the various forms of clinical data exchange have become more sophisticated, the need for more advanced interoperability with use of standardized structured codes has increased. For example, structured codes facilitate the automated identification of relevant prior imaging studies and the collection of data for radiation dose tracking. The authors review the role of imaging procedure codes in radiology departments and across the health care enterprise. Standards for radiology procedure coding are described, and the mechanisms of structured coding systems are reviewed. In particular, the structure of the RadLex™ Playbook coding system and examples of the use of this system are described. Harmonization of the RadLex Playbook system with the Logical Observation Identifiers Names and Codes standard, which is currently in progress, also is described. The benefits and challenges of adopting standardized codes-especially the difficulties in mapping local codes to standardized codes-are reviewed. Tools and strategies for mitigating these challenges, including the use of billing codes as an intermediate step in mapping, also are reviewed. In addition, the authors describe how to use the RadLex Playbook Web service application programming interface for partial automation of code mapping. © RSNA, 2017.


A Descriptive Study of the Risk Factors Associated With Catheter-Related Bloodstream Infections in the Home Parenteral Nutrition Population.
Home parenteral nutrition (HPN) is increasingly used for nutrition support after patients are discharged from the hospital. Catheter-related bloodstream infections (CR-BSI) are a common and potentially fatal complication of HPN. The risk factors for development of CR-BSI in the outpatient setting are poorly understood. We conducted an observational, retrospective study of 225 patients discharged from Barnes-Jewish Hospital on HPN between January 1, 2007, and December 31, 2009. HPN complications were defined as any cause that led to either premature discontinuation of HPN therapy or catheter replacement. CR-BSI events were identified by provider documentation. We calculated the overall complication rate and the complication rate specifically due to CR-BSI. Backward stepwise Cox regression analyses were used to assess for independent predictors of catheter-related complications. In total, 111 of 225 patients (49%) developed complications while receiving HPN (incidence = 5.06 episodes/1000 catheter days). Sixty-eight of 225 patients (30%) required catheter removal for CR-BSI (incidence = 3.10 episodes/1000 catheter days). Independent predictors of line removal specifically due to infection included anticoagulant use, ulcer or open wound, and Medicare or Medicaid insurance. The following risk factors were associated with catheter-associated complications and/or CR-BSI: the presence of ulcers, the use of systemic anticoagulants, public insurance (Medicare or Medicaid), and patient age. Independent predictors of line removal for any complication included age and anticoagulant use. Catheter-related complications were extremely common in patients receiving HPN. Healthcare providers caring for individuals who require HPN should be aware of risk factors for complications.


Short-term efficacy of physical interventions in osteoarthritic knee pain. A systematic review and meta-analysis of randomised placebo-controlled trials.
Treatment efficacy of physical agents in osteoarthritis of the knee (OAK) pain has been largely unknown, and this systematic review was aimed at assessing their short-term efficacies for pain relief. Systematic review with meta-analysis of efficacy within 1-4 weeks and at follow up at 1-12 weeks after the end of treatment. 36 randomised placebo-controlled trials (RCTs) were identified with 2434 patients where 1391 patients received active treatment. 33 trials satisfied three or more out of five methodological criteria (Jadad scale). The patient sample had a mean age of 65.1 years and mean baseline pain of 62.9 mm on a 100 mm visual analogue scale (VAS). Within 4 weeks of the commencement of treatment manual acupuncture, static magnets and ultrasound therapies did not offer statistically significant short-term pain relief over placebo. Pulsed electromagnetic fields offered a small reduction in pain of 6.9 mm [95% CI: 2.2 to 11.6] (n = 487). Transcutaneous electrical nerve stimulation (TENS, including interferential currents), electro-acupuncture (EA) and low level laser therapy (LLLT) offered clinically relevant pain relieving effects of 18.8 mm [95% CI: 9.6 to 28.1] (n = 414), 21.9 mm [95% CI: 17.3 to 26.5] (n = 73) and 17.7 mm [95% CI: 8.1 to 27.3] (n = 343) on VAS respectively versus placebo control. In a subgroup analysis of trials with assumed optimal doses, short-term efficacy increased to 22.2 mm [95% CI: 18.1 to 26.3] for TENS, and 24.2 mm [95% CI: 17.3 to 31.3] for LLLT on VAS. Follow-up data up to 12 weeks were sparse, but positive effects seemed to persist for at least 4 weeks after the course of LLLT, EA and TENS treatment was stopped. TENS, EA and LLLT administered with optimal doses in an intensive 2-4 week treatment regimen, seem to offer clinically relevant short-term pain relief for OAK.


Role of iodine-131 MIBG scanning in the management of paediatric patients with neuroblastoma.
To evaluate the role of iodine-131 metoiodobenzylguanidine (iodine-131 MIBG) scanning in the management of paediatric patients with neuroblastoma. Forty-three iodine-131 MIBG scans were performed on 26 children, 18 male and 8 female, ranging in age from 8 months to 11 years. Bone scan, computed tomography (CT) images and findings of bone marrow biopsy were compared with the iodine-131 MIBG scan findings. Of the 26 patients, 18 (69%) showed abnormal iodine-131 MIBG avidity and were proven to have a neural crest tumour on histology. The remaining 8 (31%) patients had normal iodine-131 MIBG scans, and histology showed a malignancy other than a neural crest tumour. Iodine-131 MIBG scans showed the primary site in 16 of 17 patients while CT showed 14 primary sites. In follow-up studies, the results were as follows: iodine-131 MIBG showed no evidence of disease in 4 compared with 3 on CT, persistent disease in 2 on iodine-131 MIBG and 4 on CT; recurrence in 1 on iodine-131 MIBG and 0 on CT; MIBG scans detected double the number of bony lesions compared with bone scans. The findings on iodine-131 MIBG scans and bone marrow biopsy were in agreement in 16/18 cases. Patients in whom iodine-131 MIBG scans showed disease resolution had better clinical outcomes. The findings indicate that iodine-131 MIBG scanning is useful for the diagnosis, staging, evaluation of response to therapy and detection of recurrences in patients with neuroblastoma. It exhibited a clear advantage over CT in detecting the primary site and soft issue metastases and was also superior to bone scanning in detecting skeletal metastases. It also reliably demonstrated bone marrow involvement.


The control of diuresis in the tsetse fly Glossina austeni: a preliminary investigation of the diuretic hormone.
The rate of secretion of the Malpighian tubules of Glossina austeni is controlled by a diuretic hormone. This hormone is present in the nervous tissue of the fly together with a degradative enzyme that can be activated by boiling. It is demonstrated that the Malpighian tubules are able to destroy the diuretic hormone; they may therefore participate in the control of diuresis. The diuretic hormone appears to be a heat-stable, non-dialysable, alcohol-soluble molecule, containing amino acid, glucose and sialic acid residues.


Clinical and histopathologic factors predicting recurrence and survival after pelvic exenteration for cancer of the cervix.
Between September 1969 and January 1, 1986, 143 pelvic exenterations for recurrent cervical cancer were performed by the gynecologic oncologists at the University of Alabama at Birmingham. Of this group, 78 patients underwent total pelvic exenteration, 63 patients had anterior exenteration, and two had posterior exenteration. The overall operative mortality rate was 6.3%, mostly associated with total pelvic exenteration. The 5-year survival rates were 50% overall, 63% with anterior exenteration and 42% with total exenteration. Univariate and multivariate analyses were performed to identify clinical and histopathologic factors predictive of prolonged survival. Using three clinical factors (duration from initial radiation therapy to exenteration, size of the central mass, and presence of preoperative sidewall fixation), low-, intermediate-, and high-risk groups were constructed; the 5-year survival rates for these groups were 82, 46, and 0%, respectively. Inclusion of one histopathologic factor (margin status of the surgical specimen) added to the ability to predict 2- and 5-year survival rates. The best candidates for cure by pelvic exenteration were those with recurrent small (less than 3 cm), mobile central masses who were a year or longer from the time of their previous radiation therapy. Attempts to resect bulky pelvic recurrences that impinge on the pelvic sidewall, especially in the case of persistent or early recurrent disease (within 6 months), or continuation of exenterative procedures in women known to have nodal metastases or extrapelvic spread, are generally futile. For those women falling between the two extremes, sound clinical and operative judgment is imperative in regard to selecting the treatment offering the best quality of life.


Nondrainage decreases blood transfusion need and infection rate in bilateral total knee arthroplasty.
This retrospective study enrolled 526 patients undergoing bilateral total knee arthroplasties at our institution. In nondrainage group (Group 1) of 255 patients (510 knees), a disposable elastic sterile exsanguination tourniquet (HemaClear), wound closure in layers and Jones Bandage, without pre-tourniquet removal hemostasis or Hemovac drain were used. In drainage group (Group 2) of 227 patients (454 knees), pneumatic tourniquet, post-deflation hemostasis, a Hemovac drain and Jones bandage were used. The maximal drop in hemoglobin was significantly greater in Group 2 than Group 1 (P < 0.001). Also infection rate was significantly lower in Group 1 (P = 0.017). The use of sterile tourniquet removed after wound closure without Hemovac drain decreases blood transfusion need, infection rate, tourniquet related pain and postoperative complications.


γ-tocopherol nebulization decreases oxidative stress, arginase activity, and collagen deposition after burn and smoke inhalation in the ovine model.
More than 20,000 burn injury victims suffer from smoke inhalation injury in the United States annually. In an ovine model of acute lung injury, γ-tocopherol had a beneficial effect when nebulized into the airway. We hypothesize that γ-tocopherol scavenges reactive oxygen species (ROS) and reactive nitrogen species resulting from burn and smoke inhalation injury and that these ROS/reactive nitrogen species activate the arginase pathway, leading to increased collagen deposition and decreased pulmonary function. To test this hypothesis, ewes were operatively prepared for chronic study, then they were randomly divided into groups (n = 8): uninjured, injured, or injured with nebulization (γ-tocopherol [950 mg/g] and α-tocopherol [40 mg/g] from hours 3 to 48 after the injury). The injury, under deep anesthesia, consisted of a 20% total body surface burn and 36 breaths of cotton smoke; all animals were killed after 3 weeks. Treatment increased lung γ-tocopherol at 3 weeks after γ-tocopherol nebulization compared with injured sheep (1.75 ± 0.62 nmol/g vs. 0.45 ± 0.06, P < 0.05). The expression of dimethylarginine dimethylaminohydrolase-2, which degrades asymmetrical dimethylarginine, a nitric oxide synthase inhibitor, significantly increases with γ-tocopherol treatment compared with injured sheep (P < 0.05). Arginase activity (0.15 ± 0.02 μM urea/μg protein vs. 0.24 ± 0.009, P < 0.05), ornithine aminotransferase (11,720 ± 888 vs. 13,170 ± 1,775), and collagen deposition (0.62 ± 0.12 μM hydroxyproline/μg protein vs. 1.02 ± 0.13, P < 0.05) significantly decrease with γ-tocopherol compared with injured animals without γ-tocopherol. The decreases in arginase and collagen with γ-tocopherol are associated with significantly increased diffusion capacity (P < 0.05) and decreased lung wet-to-dry ratio (P < 0.05). Smoke-induced chronic pulmonary dysfunction is mediated through the ROS/asymmetrical dimethylarginine/arginase pathway, and ROS scavengers such as γ-tocopherol may be a potential therapeutic management of burn patients with inhalation injury.


A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions.
The human T-cell lymphotropic virus type 1 (HTLV-1) infects and transforms CD4+ lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal. Here, we demonstrate that the HTLV-1 pX splice-variant p30II markedly enhances the transforming potential of Myc and transcriptionally activates the human cyclin D2 promoter, dependent upon its conserved Myc-responsive E-box enhancer elements, which are associated with increased S-phase entry and multinucleation. Enhancement of c-Myc transforming activity by HTLV-1 p30II is dependent upon the transcriptional coactivators, transforming transcriptional activator protein/p434 and TIP60, and it requires TIP60 histone acetyltransferase (HAT) activity and correlates with the stabilization of HTLV-1 p30II/Myc-TIP60 chromatin-remodeling complexes. The p30II oncoprotein colocalizes and coimmunoprecipitates with Myc-TIP60 complexes in cultured HTLV-1-infected ATLL patient lymphocytes. Amino acid residues 99 to 154 within HTLV-1 p30II interact with the TIP60 HAT, and p30II transcriptionally activates numerous cellular genes in a TIP60-dependent or TIP60-independent manner, as determined by microarray gene expression analyses. Importantly, these results suggest that p30II functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis.


Repetitive Treatment with Diluted Bee Venom Attenuates the Induction of Below-Level Neuropathic Pain Behaviors in a Rat Spinal Cord Injury Model.
The administration of diluted bee venom (DBV) into an acupuncture point has been utilized traditionally in Eastern medicine to treat chronic pain. We demonstrated previously that DBV has a potent anti-nociceptive efficacy in several rodent pain models. The present study was designed to examine the potential anti-nociceptive effect of repetitive DBV treatment in the development of below-level neuropathic pain in spinal cord injury (SCI) rats. DBV was applied into the Joksamli acupoint during the induction and maintenance phase following thoracic 13 (T13) spinal hemisection. We examined the effect of repetitive DBV stimulation on SCI-induced bilateral pain behaviors, glia expression and motor function recovery. Repetitive DBV stimulation during the induction period, but not the maintenance, suppressed pain behavior in the ipsilateral hind paw. Moreover, SCI-induced increase in spinal glia expression was also suppressed by repetitive DBV treatment in the ipsilateral dorsal spinal cord. Finally, DBV injection facilitated motor function recovery as indicated by the Basso-Beattie-Bresnahan rating score. These results indicate that the repetitive application of DBV during the induction phase not only decreased neuropathic pain behavior and glia expression, but also enhanced locomotor functional recovery after SCI. This study suggests that DBV acupuncture can be a potential clinical therapy for SCI management.


Fornix transection impairs learning of randomly changing object discriminations.
The hippocampus has a well established role in spatial memory, but increasing evidence points to a role in nonspatial aspects of memory. To investigate such a role, six macaque monkeys received a bilateral transection of the fornix to disconnect subcortical inputs and outputs of the hippocampus. An additional six macaque monkeys constituted an unoperated control group. To test the involvement of the hippocampus in nonspatial aspects of memory, both groups were trained postoperatively on four concurrent visual object discrimination problems, each problem having one rewarded object and one unrewarded. After acquisition to criterion of these discriminations, the monkeys learned five subsequent stages of discriminations using the same objects. In each of these stages, both the pairings of objects one with another, and the reward assignments for the objects, were randomly reassigned. In the initial acquisition stage, control and fornix animals were equally proficient in learning the discriminations. In the five reassigned stages, however, monkeys with fornix transection made on average three times as many errors as the controls in learning the discriminations. This impairment was noted even in trials where the reward assignments from the previous stage were maintained in the new stage. These findings are consistent with other recent evidence for a role beyond the spatial domain for the fornix in monkeys.


SU-E-I-98: PET/CT's Most-Cited 50 Articles since 2000: A Bibliometric Analysis of Classics.
Despite its relatively recent introduction to clinical practice, PET/CT has gained wide acceptance both in diagnostic and therapeutic applications. Scientific publication in PET/CT has also experienced significant development since its introduction. Bibliometric analyses allow an understanding of how this publication trend has developed at an aggregated level. Citation analysis is one of the most widely used bibliometric tools of scientometrics. Analysis of classics, defined as an articles with 100 or more citations, is common in the biomedical sciences as it reflects an article's influence in its professional and scientific community. Our objective was to identify the 50 most frequently cited classic articles in PET/CT in the past 10 years. The 50 most-cited PET/CT articles were identified by searching ISI's Web of Knowledge and Pubmed databases for all related publications from 2000 through 2010. Articles were evaluated for several characteristics such as author(s), institution, country of origin, publication year, type, and number of citations. An unadjusted categorical analysis was performed to compare all articles published in the search period. The search yielded a cumulative total of 22,554 entries for the publication period, of which 15,943 were original research articles. The 50 most-cited articles were identified from the latter sum and selected out of 73 classics. The number of citations for the top 50 classics ranged from 114 to 700. PET/CT classics appeared in three general and 12 core journals. The majority of the classics were in oncologic applications of PET/CT (62%). Articles related to diagnostic topics were 6%. The rest were focused on physics and instrumentation 24% and other basic sciences 16%. Despite its relatively short history PET/CT accumulated 73 classic articles in a decade. Such information is of importance to researchers and those who wish to study the scientific development in the field.


Occurence of a round window membrane rupture in patients with sudden sensorineural hearing loss.
Aim of the present study was to evaluate the occurence of a round window membrane rupture and the effects of hearing restoration after exploratory tympanotomy and sealing of the round window (niche) in patients with unilateral sudden deafness. Retrospective analysis of patients' charts in a tertiary referral center. Charts of 69 patients with sudden deafness followed by exploratory tympanotomy were retrospectively analyzed. Pure-tone audiometry data before and after tympanotomy were compared to determine the outcome of hearing recovery. The postoperative hearing test values were documented 3 weeks after tympanotomy. All surgical reports were reviewed with regard to the surgical technique performed and the intraoperative findings. 18.8% of the patients revealed a visible perilymphatic fistula in the round window niche. 89.8% of the patients reported no typical history for a round window membrane rupture. All patients were treated with an exploratory tympanotomy under local anesthesia and an intravenous corticosteroid treatment regimen. The majority of the surgeons used a fat plomb to cover the round window. Postoperative hearing was significantly improved compared to the preoperative hearing test data. No patient showed a worsened hearing curve after the treatment. Most patients suffering from unilateral sudden deafness had no visible perilymphatic fistula. In our study population, the majority of patients reported no typical history of a pressure elevation in the inner ear. Exploratory tympanotomy is a safe procedure that may support hearing recovery in patients with sudden deafness in addition to the established treatment regimen including high-dose steroids.


Biological functions of glucan-binding protein B of Streptococcus mutans.
Streptococcus mutans has been implicated as a major causative agent of dental caries in humans. Bacterial components associated with the adhesion phase of S. mutans include glucosyltransferases, protein antigen C and proteins that bind glucan. At least four glucan-binding proteins (Gbp) have been identified; GbpA, GbpB, GbpC and GbpD. In our previous study, the contributions of GbpA and GbpC to the virulence of S. mutans were investigated; however, the biological function of GbpB and its role in the virulence of S. mutans remain to be elucidated. Using a GbpB-deficient mutant strain (BD1), we demonstrated in the present study that GbpB has a role in the biology of S. mutans. The growth rate of BD1 was lower than that of other strains, while it was also shown to be less susceptible to phagocytosis and to form longer chains than the parental strain MT8148. In addition, electron microscope observations of the cell surfaces of BD1 showed that the cell-wall layers were obscure. These results suggest that GbpB may have an important role in cell-wall construction and be involved in cell separation and cell maintenance.